Breathing is regulated by a central neural oscillator that produces rhythmic output to the respiratory muscles. Pathological disturbances in rhythm, or dysrhythmias, are observed in the breathing pattern of children and adults with neurological or cardiopulmonary diseases. The mechanisms responsible for genesis of respiratory dysrhythmias are poorly understood. The present studies take a novel approach to this problem. The basic postulate is that the rhythm of the respiratory oscillator can be altered by a variety of stimuli. When the oscillator recovers its rhythm after such perturbations, its phase may be reset relative to the original rhythm. The amount of phase resetting is dependent upon stimulus parameters and the level of respiratory drive. The long-range hypothesis of this proposal is that respiratory dysrhythmias can be induced by stimuli that impinge upon or arise within the respiratory oscillator at a specific time in the respiratory cycle, the phase of vulnerability. Animal studies are performed in anesthetized or decerebrate preparations. Neural respiratory rhythmicity is represented by phrenic nerve activity, allowing use of open-loop experimental conditions which avoid negative chemical feedback associated with changes in ventilation. Human studies are performed in awake healthy subjects to study effects of swallowing on respiratory rhythm. Specific aims are to study: 1) the vulnerability of the respiratory oscillator to develop apneusis at low chemical drive and in response to discrete neural stimuli, and to test the hypothesis apneusis represents the respiratory oscillator's phase singularity, 2) the influence of neural maturation on phase resetting and dysrhythmias of the respiratory oscillator, and to evaluate the hypothesis that the less mature respiratory oscillator of the newborn kitten develops dysrhythmias in response to certain perturbations more readily than the mature oscillator of the adult cat, 3) the role of respiratory phase resetting in protecting the airway from aspiration during deglutition, and to determine if increasing respiratory drive by inhalation of carbon dioxide increases the vulnerability to aspirate because of discoordination of the timing of breathing and swallowing. These studies should lead to greater understanding of rhythmicity and integrative responses of the respiratory control system, and provide insight into disturbances in control mechanism that cause apnea and aspiration in clinical disease states.